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Mechanism of Anti-Cancer Activity of 9-Aminoacridine Based Drugs

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2008, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
In the tumors that maintain wild type p53 tumor suppressor gene, p53 activity is frequently inactivated by a variety of mechanisms, such as, overexpression of Mdm2 or MdmX, loss of Arf, or expression of human papilloma virus protein E6. None of these mechanisms, however, explain suppressed p53 function in the majority of renal cell carcinomas (RCC), tumors that largely have wild type p53. In our previous study, we found that a small molecule, 9-aminoacrindine (9AA) can restore p53 function in RCC and strongly stimulate activity of wild type p53 in other types of cancer cells. In addition, these compounds were found capable of inhibiting NF-kB signaling, the pathway that is constitutively active in RCC as well as in the majority of other tumor types. To determine the mechanism of simultaneous modulation of p53 and NF-kB by 9AA we compared global gene and protein expression profiles of two 9AA-treated and untreated RCC cell lines. The set of genes that changed their expression in response to 9AA treatment contained many known p53- and NF-kB targets and therefore was consistent with p53 activation and NF-kB suppression by this compound. Proteomics analysis revealed P110gamma, one of the catalytic subunits of PI3K, to be one of a few proteins that were strongly down-regulated by 9AA treatment. We further found that the observed decrease in P110gamma protein is mediated through the 9AA-induced inhibition of the PI3K/AKT/mTOR signaling pathway. Consistent with the known role of PI3K in regulation of p53 and NF-kB function, knocking down of P110gamma expression by RNA interference in RCC cells inhibited NF-kB and activated p53. Moreover, ectopic overexpression of P110gamma in 293T cells resulted in constitutive activation of NF-kB. Furthermore, overexpression of P110gamma in RCC45 cells made them less sensitive to 9AA treatment indicating, together with all the above-mentioned observations, that p110gamma is one of the targets of 9AA that mediate its modulation of p53 and NF-kB pathways in tumor cells.
Andrei Gudkov (Advisor)
David Samols (Committee Member)
Ganes Sen (Committee Member)
Hung-Ying Kao (Committee Chair)
george stark (Committee Member)
132 p.

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Citations

  • Guo, C. (2008). Mechanism of Anti-Cancer Activity of 9-Aminoacridine Based Drugs [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1216215825

    APA Style (7th edition)

  • Guo, Canhui. Mechanism of Anti-Cancer Activity of 9-Aminoacridine Based Drugs. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1216215825.

    MLA Style (8th edition)

  • Guo, Canhui. "Mechanism of Anti-Cancer Activity of 9-Aminoacridine Based Drugs." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1216215825

    Chicago Manual of Style (17th edition)